Delivery of Gases to the Nasal Airway

ABSTRACT

A delivery device for and a method of delivering gases to the nasal airway, in particular therapeutic gases and gases in combination with active substances, either as powders or liquids, for enhanced uptake of the active substances.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.12/375,115, filed on Apr. 23, 2010, which is a U.S. National phaseapplication of PCT/GB2007/002829 filed Jul. 25, 2007, the disclosure ofwhich applications are incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to a device for and a method of deliveringgases to the nasal airway, in particular therapeutic gases and gases incombination with active substances, either as powders or liquids, forenhanced uptake of the active substances.

BACKGROUND

The delivery of gases, in particular carbon dioxide, nitric oxide,oxygen and helium, to the nasal airway for therapeutic application isknown, as disclosed, for example, in WO-A-2001/003645.

Gas therapy for the treatment of headaches, allergies, asthma, and otherconditions as well as associated physiology is described in thefollowing references in the medical literature:

Carbon Dioxide Therapy

Diamond S, Migraine headache—its diagnosis and treatment. 13^(th) AnnualPracticing Physician's Approach to the Difficult Headache Patient,

Rancho Mirage, Calif. Feb. 5-19, 2000

Fisher H K et al, Am Rev Respir Dis 114(5):861, 1976

Fisher H K et al, Am Rev Respir Dis 101:855-896, 1970

Gillman M A et al, Br J Psychiatry 159:672-5, 1991

Grosshans V A et al, Z Gesamte Inn Med 42(23):667-70, 1987

Harrowes W M C et al, Fractional administration of carbon dioxide in thetreatment of neuroses, Carbon Dioxide Therapy A NeurophysiologicalTreatment of Nervous Disorders. Second Edition. L J Meduna Editor,Charles C Thomas Publisher, Springfield, Ill. 1958

Jozefowicz R F, Neurologic Manifestations of Systemic Disease7(3):605-616, 1989

La Verne A A, Dis Nery System 14:5, 1953

Leake C D et al, Calif West Med 31:20, 1929

Loevenhart A S et al, JAMA 92(11), 1929

MacRae D, Carbon dioxide in paediatrics, Carbon Dioxide Therapy ANeurophysiological Treatment of Nervous Disorders. Second Edition. L J

Meduna Editor, Charles C Thomas publisher, Springfield, Ill., 1958

Marcussen R M et al, Arch Neurol Psychiatry 63:42-51, 1950

Meduna L J, Dis Nery System 8(2), 1947

Meduna L J, J Nery & Ment Dis 108:373, 1948

Meduna L J Ed, Carbon Dioxide Therapy A Neurophysiological Treatment ofNervous Disorders. Second Edition. Charles C Thomas Publisher,Springfield, Ill. 1958

Moriarty J D, Prognosis with carbon dioxide therapy, including theepinephrine-mecholyl test (Funkenstein test), Carbon Dioxide Therapy ANeurophysiological Treatment of Nervous Disorders. Second Edition. L J

Meduna Editor, Charles C Thomas Publisher, Springfield, Ill., 1958

Moriarty J D, J Clin & Exper Psychopath 13(3), 1952

National Headache Foundation. A patients guide to migraine prevention &treatment, Chicago, Ill., August 1996.

Rodarte J R et al, Resp Physiol 17:135-145, 1973

Singh V et al, Lancet 335:1381-3, 1990

Wilkinson W E, Some clinical observations pertaining to the effects ofcarbon dioxide on the biology of mental disease, Carbon Dioxide TherapyA Neurophysiological Treatment of Nervous Disorders. Second Edition. L J

Meduna Editor, Charles C Thomas Publisher, Springfield, Ill. 1958

Wilmoth D F et al, AACN Clin Issues 7(4):473-81, 1996

Nitric Oxide Therapy

Pagano D et al, Eur J Cardiothorac Surg 10(12):1120-6, 1996

Ream R S et al, Crit Care Med 27(5):989-96, 1999

Schenk P et al, Ann Emerg Med 33(6):710-4, 1999

Helium Therapy

Hollman Get al, Crit Care Med 26(10):1731-6, 1998

Jolliet P et al, Crit Care Med 27(11):2422-9, 1999

Schaeffer E M et al, Crit Care Med 27(12):2666-70, 1999

Such gases have been shown to have a local effect on topical diseaseswhich affect the nasal mucosa, such as rhinitis, sinusitis, polyposisand allergies, and also on nerves and ganglia in relieving or treatingpain conditions, such as peripheral and local neuralgia, for example,trigeminal neuralgia.

Such gases can also have effect in relieving or treating both local andcentral pain conditions or other neurological pathologies, such asmigraine and other primary or secondary headache conditions.

SUMMARY OF THE INVENTION

As noted in WO-A-2001/003645, the delivery of therapeutic gases to thenasal airway is problematic, insofar as delivery of the gases to thenasal airway leads to inhalation of the gases.

The present inventors have also recognized that the amount of atherapeutic gas as conventionally delivered to the nasal airway cannotbe controlled.

It is one aim of the present invention to provide a device for andmethod of delivering gases to the nasal airway, in particulartherapeutic gases, which avoids the possibility of inhalation and allowsfor delivery of the gases at significantly higher concentrations.

It is another aim of the present invention to provide an improved deviceand method for delivering gases to the nasal airway, in particulartherapeutic gases and gases in combination with active substances,either as powders or liquids, for enhanced uptake of the activesubstances.

In one aspect the present invention provides a delivery device forproviding a therapeutic gas to the nasal airway of a subject, thedelivery device comprising: a nosepiece for fitting to one nostril ofthe subject; a mouthpiece through which the subject in use exhales andwhich is fluidly connected to the nosepiece; and a scrubber which isoperative at least to reduce the concentration of at least one gas froman exhaled breath of the subject as delivered through the mouthpiece andprovide a gas flow to the nosepiece which has an increased concentrationof at least one other, therapeutic gas which provides a therapeuticeffect.

In one embodiment the scrubber is operative to reduce the concentrationof at least two gases from an exhaled breath of the subject.

In one embodiment the at least one gas comprises nitrogen.

In one embodiment the at least one gas comprises oxygen.

In one embodiment the at least one other, therapeutic gas comprisesoxygen.

In one embodiment the at least one gas comprises carbon dioxide.

In one embodiment the at least one other, therapeutic gas comprisescarbon dioxide.

Preferably, the scrubber is operative to provide a gas flow which has aconcentration of the at least one other, therapeutic gas of at least 10vol %.

More preferably, the scrubber is operative to provide a gas flow whichhas a concentration of the at least one other, therapeutic gas of atleast 15 vol %.

Still more preferably, the scrubber is operative to provide a gas flowwhich has a concentration of the at least one other, therapeutic gas ofat least 20 vol %.

Yet more preferably, the scrubber is operative to provide a gas flowwhich has a concentration of the at least one other, therapeutic gas ofat least 30 vol %.

Yet still more preferably, the scrubber is operative to provide a gasflow which has a concentration of the at least one other, therapeuticgas of at least 40 vol %.

Still yet more preferably, the scrubber is operative to provide a gasflow which has a concentration of the at least one other, therapeuticgas of at least 50 vol %.

In one embodiment the delivery device further comprises: a furthernosepiece for fitting to the other nostril of the subject; and apressure regulator which is fluidly connected to the other nosepiece,such as to provide for control of a pressure regime within the nasalairway of the subject.

In another aspect the present invention provides a delivery device forproviding a therapeutic gas to the nasal airway of a subject, thedelivery device comprising: a nosepiece for fitting to one nostril ofthe subject; and a therapeutic gas supply unit for supplying at leastone therapeutic gas to the nosepiece, such as to provide for delivery ofthe at least one therapeutic gas to the nasal airway of the subject.

In one embodiment the at least one therapeutic gas comprises carbondioxide.

In one embodiment the at least one therapeutic gas comprises nitricoxide.

In one embodiment the at least one therapeutic gas comprises oxygen.

In one embodiment the at least one therapeutic gas comprises helium.

In one embodiment the delivery device further comprises: a mouthpiecethrough which the subject in use exhales.

In one embodiment the mouthpiece is fluidly connected to the nosepiece,such that a gas flow as developed from an exhalation breath of thesubject is delivered through the nosepiece.

In another embodiment the mouthpiece is fluidly separated from thenosepiece, such that a gas flow as developed from an exhalation breathof the subject is not delivered through the nosepiece.

In one embodiment the therapeutic gas supply unit comprises atherapeutic gas generator which is operative to generate at least onetherapeutic gas.

In one embodiment the therapeutic gas generator is operative to generateat least one therapeutic gas on exhalation by the subject through themouthpiece.

In one embodiment the therapeutic gas generator comprises a therapeuticgas generating agent which reacts to generate the at least onetherapeutic gas.

In one embodiment the therapeutic gas generator comprises a therapeuticgas generating agent which is reactive to moisture in the exhalationbreath of the subject.

In another embodiment the therapeutic gas supply unit comprises a gassupply which is actuatable to deliver at least one therapeutic gas.

In one embodiment the therapeutic gas supply unit comprises abreath-actuated release mechanism which actuates the gas supply todeliver at least one therapeutic gas in response to exhalation by thesubject through the mouthpiece.

Preferably, the gas supply unit provides a gas flow which has aconcentration of the at least one therapeutic gas of at least 10 vol %.

More preferably, the gas supply unit provides a gas flow which has aconcentration of the at least one therapeutic gas of at least 15 vol %.

Still more preferably, the gas supply unit provides a gas flow which hasa concentration of the at least one therapeutic gas of at least 20 vol%.

Yet more preferably, the gas supply unit provides a gas flow which has aconcentration of the at least one therapeutic gas of at least 30 vol %.

Still yet more preferably, the gas supply unit provides a gas flow whichhas a concentration of the at least one therapeutic gas of at least 40vol %.

Yet still more preferably, the gas supply unit provides a gas flow whichhas a concentration of the at least one therapeutic gas of at least 50vol %.

In one embodiment the delivery device further comprises: a furthernosepiece for fitting to the other nostril of the subject; and apressure regulator which is fluidly connected to the other nosepiece,such as to provide for control of a pressure regime within the nasalairway of the subject.

In a further aspect the present invention provides a delivery device forproviding a substance and an uptake enhancing gas, which acts toincrease the uptake of the substance, to the nasal airway of a subject,the delivery device comprising: a nosepiece for fitting to one nostrilof the subject; a mouthpiece through which the subject in use exhalesand which is fluidly connected to the nosepiece; a substance supply unitwhich is fluidly connected to the nosepiece and operative to supplysubstance; and a scrubber which is operative at least to reduce theconcentration of at least one gas from an exhaled breath of the subjectas delivered through the mouthpiece and provide a gas flow to thenosepiece which has an increased concentration of at least one other,uptake enhancing gas which acts to increase the uptake of substance asdelivered by the substance supply unit.

In one embodiment the substance supply unit is configured to deliver anaerosol spray.

In one embodiment the aerosol spray comprises a liquid aerosol spray.

In another embodiment the aerosol spray comprises a powder aerosolspray.

In another embodiment the substance supply unit is configured to delivera liquid jet.

In a further embodiment the substance supply unit is configured todeliver a powder jet.

In one embodiment the substance supply unit is a breath-actuated unitwhich is actuated in response to exhalation by the subject through themouthpiece.

In one embodiment the substance supply unit is actuatable in response togeneration of a predeterminable flow rate through the nosepiece.

In another embodiment the substance supply unit is actuatable inresponse to generation of a predeterminable pressure at the nosepiece.

In one embodiment the scrubber is operative to reduce the concentrationof at least two gases from an exhaled breath of the subject.

In one embodiment the at least one gas comprises nitrogen.

In one embodiment the at least one gas comprises oxygen.

In one embodiment the at least one other, uptake enhancing gas comprisesoxygen.

In one embodiment the at least one gas comprises carbon dioxide.

In one embodiment the at least one, other uptake enhancing gas comprisescarbon dioxide.

Preferably, the scrubber is operative to provide a gas flow which has aconcentration of the at least one other, uptake enhancing gas of atleast 10 vol %.

More preferably, the scrubber is operative to provide a gas flow whichhas a concentration of the at least one, other uptake enhancing gas ofat least 15 vol %.

Still more preferably, the scrubber is operative to provide a gas flowwhich has a concentration of the at least one, other uptake enhancinggas of at least 20 vol %.

Yet more preferably, the scrubber is operative to provide a gas flowwhich has a concentration of the at least one, other uptake enhancinggas of at least 30 vol %.

Still yet more preferably, the scrubber is operative to provide a gasflow which has a concentration of the at least one, other uptakeenhancing gas of at least 40 vol %.

Yet still more preferably, the scrubber is operative to provide a gasflow which has a concentration of the at least one, other uptakeenhancing gas of at least 50 vol %.

In one embodiment the delivery device further comprises: a furthernosepiece for fitting to the other nostril of the subject; and apressure regulator which is fluidly connected to the other nosepiece,such as to provide for control of a pressure regime within the nasalairway of the subject.

In a still further aspect the present invention provides a deliverydevice for providing a substance and an uptake enhancing gas, which actsto increase the uptake of the substance, to the nasal airway of asubject, the delivery device comprising: a nosepiece for fitting to onenostril of the subject; a substance supply unit which is fluidlyconnected to the nosepiece and operative to supply substance; and anuptake enhancing gas supply unit for supplying at least one uptakeenhancing gas to the nosepiece, such as to provide for delivery of theat least one uptake enhancing gas to the nasal airway of the subject,which acts to increase the uptake of substance as delivered by thesubstance supply unit.

In one embodiment the substance supply unit is configured to deliver anaerosol spray.

In one embodiment the aerosol spray comprises a liquid aerosol spray.

In another embodiment the aerosol spray comprises a powder aerosolspray.

In another embodiment the substance supply unit is configured to delivera liquid jet.

In a further embodiment the substance supply unit is configured todeliver a powder jet.

In one embodiment the at least one uptake enhancing gas comprises carbondioxide.

In one embodiment the at least one uptake enhancing gas comprises nitricoxide.

In one embodiment the at least one uptake enhancing gas comprisesoxygen.

In one embodiment the at least one uptake enhancing gas compriseshelium.

In one embodiment the delivery device further comprises: a mouthpiecethrough which the subject in use exhales.

In one embodiment the mouthpiece is fluidly connected to the nosepiece,such that a gas flow as developed from an exhalation breath of thesubject is delivered through the nosepiece.

In another embodiment the mouthpiece is fluidly separated from thenosepiece, such that a gas flow as developed from an exhalation breathof the subject is not delivered through the nosepiece.

In one embodiment the uptake enhancing gas supply unit comprises anuptake enhancing gas generator which is operative to generate at leastone uptake enhancing gas.

In one embodiment the uptake enhancing gas generator is operative togenerate at least one uptake enhancing gas on exhalation by the subjectthrough the mouthpiece.

In one embodiment the uptake enhancing gas generator comprises an uptakeenhancing gas generating agent which reacts to generate the at least oneuptake enhancing gas.

In one embodiment the uptake enhancing gas generator comprises an uptakeenhancing gas generating agent which is reactive to moisture in theexhalation breath of the subject.

In another embodiment the uptake enhancing gas supply unit comprises agas supply which is actuatable to deliver at least one uptake enhancinggas.

In one embodiment the uptake enhancing gas supply unit comprises abreath-actuated release mechanism which actuates the gas supply todeliver at least one uptake enhancing gas in response to exhalation bythe subject through the mouthpiece.

Preferably, the delivery device provides a gas flow which has aconcentration of the at least one uptake enhancing gas of at least 10vol %.

More preferably, the delivery device provides a gas flow which has aconcentration of the at least one uptake enhancing gas of at least 15vol %.

Still more preferably, the delivery device provides a gas flow which hasa concentration of the at least one uptake enhancing gas of at least 20vol %.

Yet more preferably, the delivery device provides a gas flow which has aconcentration of the at least one uptake enhancing gas of at least 30vol %.

Still yet more preferably, the delivery device provides a gas flow whichhas a concentration of the at least one uptake enhancing gas of at least40 vol %.

Yet still more preferably, the delivery device provides a gas flow whichhas a concentration of the at least one uptake enhancing gas of at least50 vol %.

In one embodiment the delivery device further comprises: a furthernosepiece for fitting to the other nostril of the subject; and apressure regulator which is fluidly connected to the other nosepiece,such as to provide for control of a pressure regime within the nasalairway of the subject.

In a yet further aspect the present invention provides a delivery devicefor providing a substance and an uptake enhancing gas, which acts toincrease the uptake of the substance, to the nasal airway of a subject,the delivery device comprising: a nosepiece for fitting to one nostrilof the subject; and a delivery unit which is fluidly connected to thenosepiece and operative to supply a substance and an uptake enhancingagent, such as to provide for delivery of the substance and the uptakeenhancing agent to the nasal airway of the subject, which acts toincrease the uptake of the substance as delivered by the substancesupply unit.

In one embodiment the delivery unit is configured to deliver an aerosolspray.

In one embodiment the aerosol spray comprises a liquid aerosol spray.

In another embodiment the aerosol spray comprises a powder aerosolspray.

In another embodiment the delivery unit is configured to deliver aliquid jet.

In a further embodiment the delivery unit is configured to deliver apowder jet.

In one embodiment the uptake enhancing agent comprises at least oneuptake enhancing gas.

In one embodiment the delivery unit is operative to supply the substanceand the at least one uptake enhancing gas from a container, such as acapsule or blister.

In another embodiment the uptake enhancing agent comprises an uptakeenhancing gas generating agent which is delivered together with thesubstance to the nasal airway and yields at least one uptake enhancinggas on exposure to moisture on surfaces of the nasal airway.

In one embodiment the delivery unit is operative to supply the substanceand the at least one uptake enhancing gas generating agent from acontainer, such as a capsule or blister.

In a further embodiment the uptake enhancing agent comprises an uptakeenhancing gas generating agent which is contained in the delivery deviceand yields at least one uptake enhancing gas on exposure to moisture inthe exhalation breath of the subject.

In one embodiment the delivery unit is operative to supply the substancefrom a container which contains the uptake enhancing gas generatingagent.

In one embodiment the at least one uptake enhancing gas comprises carbondioxide.

In one embodiment the at least one uptake enhancing gas comprises nitricoxide.

In one embodiment the at least one uptake enhancing gas comprisesoxygen.

In one embodiment the at least one uptake enhancing gas compriseshelium.

In one embodiment the delivery device further comprises: a mouthpiecethrough which the subject in use exhales.

In one embodiment the mouthpiece is fluidly connected to the nosepiece,such that a gas flow as developed from an exhalation breath of thesubject is delivered through the nosepiece.

In another embodiment the mouthpiece is fluidly separated from thenosepiece, such that a gas flow as developed from an exhalation breathof the subject is not delivered through the nosepiece.

Preferably, the delivery device provides a gas flow which has aconcentration of the at least one uptake enhancing gas of at least 10vol %.

More preferably, the delivery device provides a gas flow which has aconcentration of the at least one uptake enhancing gas of at least 15vol %.

Still more preferably, the delivery device provides a gas flow which hasa concentration of the at least one uptake enhancing gas of at least 20vol %.

Yet more preferably, the delivery device provides a gas flow which has aconcentration of the at least one uptake enhancing gas of at least 30vol %.

Still yet more preferably, the delivery device provides a gas flow whichhas a concentration of the at least one uptake enhancing gas of at least40 vol %.

Yet still more preferably, the delivery device provides a gas flow whichhas a concentration of the at least one uptake enhancing gas of at least50 vol %.

In one embodiment the delivery device further comprises: a furthernosepiece for fitting to the other nostril of the subject; and apressure regulator which is fluidly connected to the other nosepiece,such as to provide for control of a pressure regime within the nasalcavity of the subject.

In yet another aspect the present invention provides a method ofproviding a therapeutic gas to the nasal airway of a subject, comprisingthe steps of: fitting a nosepiece to one nostril of the subject; and thesubject exhaling through a mouthpiece which is fluidly connected to thenosepiece and a scrubber which at least reduces the concentration of atleast one gas from the exhaled breath of the subject and provides a gasflow to the nosepiece which has an increased concentration of at leastone other, therapeutic gas which provides a therapeutic effect.

In one embodiment the scrubber reduces the concentration of at least twogases from the exhaled breath of the subject.

In one embodiment the at least one gas comprises nitrogen.

In one embodiment the at least one gas comprises oxygen.

In one embodiment the at least one other, therapeutic gas comprisesoxygen.

In one embodiment the at least one gas comprises carbon dioxide.

In one embodiment the at least one other, therapeutic gas comprisescarbon dioxide.

Preferably, the scrubber provides a gas flow which has a concentrationof the at least one other, therapeutic gas of at least 10 vol %.

More preferably, the scrubber provides a gas flow which has aconcentration of the at least one other, therapeutic gas of at least 15vol %.

Still more preferably, the scrubber provides a gas flow which has aconcentration of the at least one other, therapeutic gas of at least 20vol %.

Yet more preferably, the scrubber provides a gas flow which has aconcentration of the at least one other, therapeutic gas of at least 30vol %.

Still yet more preferably, the scrubber provides a gas flow which has aconcentration of the at least one other, therapeutic gas of at least 40vol %.

Yet still more preferably, the scrubber provides a gas flow which has aconcentration of the at least one other, therapeutic gas of at least 50vol %.

In one embodiment the method further comprises the step of: fitting afurther nosepiece to the other nostril of the subject and a pressureregulator to the other nosepiece, such as to control a pressure regimewithin the nasal airway of the subject.

In a still further aspect the present invention provides a method ofproviding a therapeutic gas to the nasal airway of a subject, comprisingthe steps of: fitting a nosepiece to one nostril of the subject; andsupplying at least one therapeutic gas to the nosepiece, such as toprovide for delivery of the at least one therapeutic gas to the nasalairway of the subject.

In one embodiment the at least one therapeutic gas comprises carbondioxide.

In one embodiment the at least one therapeutic gas comprises nitricoxide.

In one embodiment the at least one therapeutic gas comprises oxygen.

In one embodiment the at least one therapeutic gas comprises helium.

In one embodiment the method further comprises the step of: the subjectexhaling through a mouthpiece.

In one embodiment the mouthpiece is fluidly connected to the nosepiece,such that a gas flow as developed from the exhalation breath of thesubject is delivered through the nosepiece.

In another embodiment the mouthpiece is fluidly separated from thenosepiece, such that a gas flow as developed from the exhalation breathof the subject is not delivered through the nosepiece.

In one embodiment the step of supplying at least one therapeutic gascomprises the step of: generating at least one therapeutic gas onexhalation by the subject through the mouthpiece.

In one embodiment the step of supplying at least one therapeutic gascomprises the step of: generating at least one therapeutic gas from atherapeutic gas generating agent which reacts to generate the at leastone therapeutic gas.

In one embodiment the therapeutic gas generating agent is reactive tomoisture in the exhalation breath of the subject.

In another embodiment the step of supplying at least one therapeutic gascomprises the step of: actuating a gas supply to supply at least onetherapeutic gas.

In one embodiment the step of supplying at least one therapeutic gascomprises the step of: actuating a gas supply to supply at least onetherapeutic gas in response to exhalation by the subject through themouthpiece.

Preferably, the at least one therapeutic gas is supplied in a gas flowat a concentration of at least 10 vol %.

More preferably, the at least one therapeutic gas is supplied in a gasflow at a concentration of at least 15 vol %.

Still more preferably, the at least one therapeutic gas is supplied in agas flow at a concentration of at least 20 vol %.

Yet more preferably, the at least one therapeutic gas is supplied in agas flow at a concentration of at least 30 vol %.

Still yet more preferably, the at least one therapeutic gas is suppliedin a gas flow at a concentration of at least 40 vol %.

Yet still more preferably, the at least one therapeutic gas is suppliedin a gas flow at a concentration of at least 50 vol %.

In one embodiment the method further comprises the step of: fitting afurther nosepiece to the other nostril of the subject and a pressureregulator to the other nosepiece, such as to control a pressure regimewithin the nasal airway of the subject.

In a yet further aspect the present invention provides a method ofproviding a substance and an uptake enhancing gas, which acts toincrease the uptake of the substance, to the nasal airway of a subject,comprising the steps of: fitting a nosepiece to one nostril of thesubject; supplying a substance to the nosepiece; and the subjectexhaling through a mouthpiece which is fluidly connected to thenosepiece and a scrubber which at least reduces the concentration of atleast one gas from the exhaled breath of the subject and provides a gasflow to the nosepiece which has an increased concentration of at leastone other, uptake enhancing gas which acts to increase the uptake ofsubstance.

In one embodiment the substance is delivered as an aerosol spray.

In one embodiment the aerosol spray comprises a liquid aerosol spray.

In another embodiment the aerosol spray comprises a powder aerosolspray.

In another embodiment the substance is delivered as a liquid jet.

In a further embodiment the substance is delivered as a powder jet.

In one embodiment the step of supplying substance comprises the step of:supplying substance to the nosepiece in response to exhalation by thesubject through the mouthpiece.

In one embodiment the substance is supplied in response to generation ofa predeterminable flow rate through the nosepiece.

In another embodiment the substance is supplied in response togeneration of a predeterminable pressure at the nosepiece.

In one embodiment the scrubber reduces the concentration of at least twogases from the exhaled breath of the subject.

In one embodiment the at least one gas comprises nitrogen.

In one embodiment the at least one gas comprises oxygen.

In one embodiment the at least one other, uptake enhancing gas comprisesoxygen.

In one embodiment the at least one gas comprises carbon dioxide.

In one embodiment the at least one, other uptake enhancing gas comprisescarbon dioxide.

Preferably, the scrubber provides a gas flow which has a concentrationof the at least one other, uptake enhancing gas of at least 10 vol %.

More preferably, the scrubber provides a gas flow which has aconcentration of the at least one, other uptake enhancing gas of atleast 15 vol %.

Still more preferably, the scrubber provides a gas flow which has aconcentration of the at least one, other uptake enhancing gas of atleast 20 vol %.

Yet more preferably, the scrubber provides a gas flow which has aconcentration of the at least one, other uptake enhancing gas of atleast 30 vol %.

Still yet more preferably, the scrubber provides a gas flow which has aconcentration of the at least one, other uptake enhancing gas of atleast 40 vol %.

Yet still more preferably, the scrubber provides a gas flow which has aconcentration of the at least one, other uptake enhancing gas of atleast 50 vol %.

In one embodiment the method further comprises the step of: fitting afurther nosepiece to the other nostril of the subject and a pressureregulator to the other nosepiece, such as to control a pressure regimewithin the nasal airway of the subject.

In still another aspect the present invention provides a method ofproviding a substance and an uptake enhancing gas, which acts toincrease the uptake of the substance, to the nasal airway of a subject,comprising the steps of: fitting a nosepiece to one nostril of thesubject; supplying a substance to the nosepiece, such as to provide fordelivery of the substance to the nasal airway of the subject; andsupplying at least one uptake enhancing gas to the nosepiece, such as toprovide for delivery of the at least one uptake enhancing gas to thenasal airway of the subject, which acts to increase the uptake ofsubstance.

In one embodiment the substance is delivered as an aerosol spray.

In one embodiment the aerosol spray comprises a liquid aerosol spray.

In another embodiment the aerosol spray comprises a powder aerosolspray.

In another embodiment the substance is delivered as a liquid jet.

In a further embodiment the substance is delivered as a powder jet.

In one embodiment the at least one uptake enhancing gas comprises carbondioxide.

In one embodiment the at least one uptake enhancing gas comprises nitricoxide.

In one embodiment the at least one uptake enhancing gas comprisesoxygen.

In one embodiment the at least one uptake enhancing gas compriseshelium.

In one embodiment the method further comprises the step of: the subjectexhaling through a mouthpiece.

In one embodiment the mouthpiece is fluidly connected to the nosepiece,such that a gas flow as developed from the exhalation breath of thesubject is delivered through the nosepiece.

In another embodiment the mouthpiece is fluidly separated from thenosepiece, such that a gas flow as developed from the exhalation breathof the subject is not delivered through the nosepiece.

In one embodiment the step of supplying at least one uptake enhancinggas comprises the step of: generating at least one uptake enhancing gason exhalation by the subject through the mouthpiece.

In one embodiment the step of supplying at least one uptake enhancinggas comprises the step of: generating at least one uptake enhancing gasfrom an uptake enhancing gas generating agent which reacts to generatethe at least one uptake enhancing gas.

In one embodiment the uptake enhancing gas generating agent is reactiveto moisture in the exhalation breath of the subject.

In another embodiment the step of supplying at least one uptakeenhancing gas comprises the step of: actuating a gas supply to supply atleast one uptake enhancing gas.

In one embodiment the step of supplying at least one uptake enhancinggas comprises the step of: actuating a gas supply to supply at least oneuptake enhancing gas in response to exhalation by the subject throughthe mouthpiece.

Preferably, the at least one uptake enhancing gas is supplied in a gasflow at a concentration of at least 10 vol %.

More preferably, the at least one uptake enhancing gas is supplied in agas flow at a concentration of at least 15 vol %.

Still more preferably, the at least one uptake enhancing gas is suppliedin a gas flow at a concentration of at least 20 vol %.

Yet more preferably, the at least one uptake enhancing gas is suppliedin a gas flow at a concentration of at least 30 vol %.

Still yet more preferably, the at least one uptake enhancing gas issupplied in a gas flow at a concentration of at least 40 vol %.

Yet still more preferably, the at least one uptake enhancing gas issupplied in a gas flow at a concentration of at least 50 vol %.

In one embodiment the method further comprises the step of: fitting afurther nosepiece to the other nostril of the subject and a pressureregulator to the other nosepiece, such as to control a pressure regimewithin the nasal airway of the subject.

In still yet another aspect the present invention provides a method ofproviding a substance and an uptake enhancing gas, which acts toincrease the uptake of the substance, to the nasal airway of a subject,comprising the steps of: fitting a nosepiece to one nostril of thesubject; and supplying a substance and an uptake enhancing agent to thenosepiece, such as to provide for delivery of the substance and theuptake enhancing agent to the nasal airway of the subject, which acts toincrease the uptake of the substance.

In one embodiment one or both of the substance and the uptake enhancingagent are delivered as an aerosol spray.

In one embodiment the aerosol spray comprises a liquid aerosol spray.

In one embodiment the aerosol spray comprises a powder aerosol spray.

In another embodiment one or both of the substance and the uptakeenhancing agent are delivered as a liquid jet.

In a further embodiment one or both of the substance and the uptakeenhancing agent are delivered as a powder jet.

In one embodiment the uptake enhancing agent comprises at least oneuptake enhancing gas.

In one embodiment the substance and the at least one uptake enhancinggas are delivered from a container, such as a capsule or blister.

In another embodiment the uptake enhancing agent comprises an uptakeenhancing gas generating agent which is delivered together with thesubstance to the nasal airway and yields at least one uptake enhancinggas on exposure to moisture on surfaces of the nasal airway.

In one embodiment the substance and the at least one uptake enhancinggas generating agent are delivered from a container, such as a capsuleor blister.

In a further embodiment the uptake enhancing agent comprises an uptakeenhancing gas generating agent which is contained upstream of thenosepiece and yields at least one uptake enhancing gas on exposure tomoisture in the exhalation breath of the subject.

In one embodiment the substance is delivered from a container, such as acapsule or a blister, which contains the uptake enhancing gas generatingagent.

In one embodiment the at least one uptake enhancing gas comprises carbondioxide.

In one embodiment the at least one uptake enhancing gas comprises nitricoxide.

In one embodiment the at least one uptake enhancing gas comprisesoxygen.

In one embodiment the at least one uptake enhancing gas compriseshelium.

In one embodiment the method further comprises the step of: the subjectexhaling through a mouthpiece.

In one embodiment the mouthpiece is fluidly connected to the nosepiece,such that a gas flow as developed from the exhalation breath of thesubject is delivered through the nosepiece.

In another embodiment the mouthpiece is fluidly separated from thenosepiece, such that a gas flow as developed from the exhalation breathof the subject is not delivered through the nosepiece.

Preferably, the at least one uptake enhancing gas is supplied in a gasflow at a concentration of at least 10 vol %.

More preferably, the at least one uptake enhancing gas is supplied in agas flow at a concentration of at least 15 vol %.

Still more preferably, the at least one uptake enhancing gas is suppliedin a gas flow at a concentration of at least 20 vol %.

Yet more preferably, the at least one uptake enhancing gas is suppliedin a gas flow at a concentration of at least 30 vol %.

Still yet more preferably, the at least one uptake enhancing gas issupplied in a gas flow at a concentration of at least 40 vol %.

Yet still more preferably, the at least one uptake enhancing gas issupplied in a gas flow at a concentration of at least 50 vol %.

In one embodiment the method further comprises the step of: fitting afurther nosepiece to the other nostril of the subject and a pressureregulator to the other nosepiece, such as to control a pressure regimewithin the nasal airway of the subject.

In a still further aspect the present invention provides a deliverydevice for delivering a gas to the nasal airway of a subject, inparticular a therapeutic gas or an uptake enhancing gas in combinationwith an active substance, either as a powder or liquid, for enhanceduptake of the active substance.

In still another aspect the present invention provides a method ofdelivering a gas to the nasal airway of a subject, in particular atherapeutic gas or an uptake enhancing gas in combination with an activesubstance, either as a powder or liquid, for enhanced uptake of theactive substance.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the present invention will now be describedhereinbelow by way of example only with reference to the accompanyingdrawings, in which:

FIG. 1 illustrates a delivery device in accordance with a firstembodiment of the present invention;

FIG. 2 illustrates a delivery device in accordance with a secondembodiment of the present invention;

FIG. 3 illustrates a delivery device in accordance with a thirdembodiment of the present invention;

FIG. 4 illustrates a delivery device in accordance with a fourthembodiment of the present invention;

FIG. 5 illustrates a delivery device in accordance with a fifthembodiment of the present invention;

FIG. 6 illustrates a delivery device in accordance with a sixthembodiment of the present invention;

FIG. 7 illustrates a delivery device in accordance with a seventhembodiment of the present invention;

FIG. 8 illustrates a delivery device in accordance with an eighthembodiment of the present invention; and

FIG. 9 illustrates a delivery device in accordance with a ninthembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 illustrates a delivery device in accordance with a firstembodiment of the present invention.

The delivery device comprises a nosepiece 21 for fitting in one nostrilof a subject, in this embodiment to provide a fluid-tight sealtherewith, a mouthpiece 23 through which the subject exhales, and a flowchannel 25 fluidly connecting the nosepiece 21 and the mouthpiece 23.

The delivery device further comprises a scrubber 27 which is disposed inthe flow channel 25 such as to remove one or more gases, in thisembodiment one or both of oxygen and nitrogen, from the exhaled air andprovide a gas flow which has an increased concentration of at least onegas, in this embodiment a concentration of carbon dioxide, which isincreased to a concentration which provides a therapeutic effect.

Alveolar air typically has a composition of N2—74.9 vol %, O2—13.6 vol %and CO2—5.3 vol %, which has a significantly increased concentration ofcarbon dioxide as compared to atmospheric air, which typically has thecomposition of N2—78.62 vol % O2—20.84 vol % and CO2—0.04 vol %. Throughuse of the scrubber 27 to remove nitrogen and oxygen from the exhaledair, the concentration of carbon dioxide in the delivered gas flow canbe increased significantly.

In one embodiment the scrubber 27 provides for a gas flow which has aconcentration of therapeutic gas of at least 10 vol %, preferably atleast 15 vol %, more preferably at least 20 vol %, still more preferablyat least 30 vol %, yet more preferably at least 40 vol %, and yet stillmore preferably at least 50 vol %.

In one embodiment the scrubber 27 could be configured to provide avisual indication, such as by way of changing colour, to indicate whenthe efficiency of the scrubber 27 has reduced below a predeterminedthreshold.

With this configuration, a gas flow as developed by the exhalationbreath of a subject is delivered through the nasal airway of the subjectwhilst the oropharyngeal velum of the subject is closed, therebyproviding for the delivery of at least one therapeutic gas to the nasalairway and preventing inhalation of the at least one therapeutic gas.

FIG. 2 illustrates a delivery device in accordance with a secondembodiment of the present invention.

The delivery device comprises a nosepiece 121 for fitting in one nostrilof a subject, in this embodiment to provide a fluid-tight sealtherewith, a mouthpiece 123 through which the subject exhales, and aflow channel 125 fluidly connecting the nosepiece 121 and the mouthpiece123.

The delivery device further comprises a scrubber 127 which is disposedin the flow channel 125 such as to remove one or more gases, in thisembodiment one or both of oxygen and nitrogen, from the exhaled air andprovide a gas flow which has an increased concentration of at least onegas, in this embodiment a concentration of carbon dioxide, whichprovides for enhanced uptake of a substance as delivered to the nasalairway, as will be described in more detail hereinbelow.

Alveolar air typically has a composition of N2—74.9 vol %, O2—13.6 vol %and CO2—5.3 vol %, which has a significantly increased concentration ofcarbon dioxide as compared to atmospheric air, which typically has thecomposition of N2—78.62 vol % O2—20.84 vol % and CO2—0.04 vol %. Throughuse of the scrubber 127 to remove nitrogen and oxygen from the exhaledair, the concentration of carbon dioxide in the delivered gas flow canbe increased significantly.

In one embodiment the scrubber 127 provides for a gas flow which has aconcentration of the uptake enhancing gas of at least 10 vol %,preferably at least 15 vol %, more preferably at least 20 vol %, stillmore preferably at least 30 vol %, yet more preferably at least 40 vol%, and yet still more preferably at least 50 vol %.

The delivery device further comprises a substance supply unit 129 forsupplying metered doses of an active substance for delivery to the nasalairway of the subject.

In one embodiment the substance supply unit 129 is configured to deliveran aerosol spray, either as a liquid or a powder aerosol spray, but inan alternative embodiment could be configured to deliver a jet, that is,as a column of the substance, either as a liquid or powder jet.

In this embodiment the substance supply unit 129 comprises a mechanicaldelivery pump, in particular a liquid delivery pump or a powder deliverypump, which delivers metered doses of substance, on actuation thereof.

In another alternative embodiment the substance supply unit 129 couldcomprise a dry powder delivery unit which delivers metered doses ofsubstance, as a dry powder, on actuation thereof. In one embodiment thesubstance supply unit 129 could provide for delivery of substance from acontainer, such as a capsule or blister.

In yet another alternative embodiment the substance supply unit 129could comprise an aerosol canister which delivers metered volumes of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In this embodiment the substance supply unit 129 is a multi-dose unitfor delivering a plurality of metered doses of the active substance. Inanother embodiment the substance supply unit 129 could be a single-doseunit for delivering a single metered dose of the active substance.

The substance supply unit 129 is pre-primeable, in this embodiment byloading a resilient element, and includes a breath-actuated releasemechanism which, when triggered, releases the resilient element andactuates the substance supply unit 129 to deliver a metered dose of theactive substance.

In this embodiment the trigger mechanism is configured to causeactuation of the substance supply unit 129 on generation of apredetermined flow rate through the flow channel 125.

In an alternative embodiment the trigger mechanism could be configuredto cause actuation of the substance supply unit 129 on generation of apredetermined pressure in the flow channel 125.

With this configuration, a gas flow as developed by the exhalationbreath of a subject is delivered through the nasal airway of the subjectwhilst the oropharyngeal velum of the subject is closed, with the velumbeing closed by the positive pressure as created in the oral cavity onexhalation, and a metered dose of an active substance is delivered intothe nasal airway on generation of a predetermined flow rate through thenasal airway, or in an alternative embodiment a predetermined pressurein the nasal airway.

The gas flow as delivered through the nasal airway includes at least oneuptake enhancing gas, in this embodiment carbon dioxide, which providesfor enhanced uptake of the active substance, and inhalation of this gasis prevented by closure of the velum.

FIG. 3 illustrates a delivery device in accordance with a thirdembodiment of the present invention.

The delivery device comprises a nosepiece 221 for fitting in one nostrilof a subject, in this embodiment to provide a fluid-tight sealtherewith, a mouthpiece 223 through which the subject exhales, and aflow channel 225 fluidly connecting the nosepiece 221 and the mouthpiece223.

The delivery device further comprises a gas generation unit 227 which isdisposed in the flow channel 225 and provides for the generation of atherapeutic gas, in this embodiment carbon dioxide, which is entrainedby the gas flow, as developed by the exhalation breath, into the nasalairway, and thereby provides a therapeutic effect on delivery into thenasal airway.

In this embodiment the gas generation unit 227 contains a powderedagent, here a mixture of a carbonate or bicarbonate salt, such as sodiumbicarbonate, and an acid, such as citric acid, which, when exposed tomoisture as contained in the exhaled breath, reacts to generate thetherapeutic gas, here carbon dioxide. In addition to generating atherapeutic gas, the gas generation unit 227 has the particular benefitof acting as a moisture trap.

In this embodiment the powdered agent is contained in an air permeablemember, typically a sachet, which can be replaced after one or more usesof the delivery device.

In this embodiment the gas generation unit 227 is disposed at anupstream end of the flow channel 225, such that substantially nocondensation of moisture from the exhalation breath occurs prior to theexhalation breath being exposed to the gas generation unit 227.

In one embodiment the gas generation unit 227 provides a gas flow whichhas a concentration of the therapeutic gas of at least 10 vol %,preferably at least 15 vol %, more preferably at least 20 vol %, stillmore preferably at least 30 vol %, yet more preferably at least 40 vol%, and yet still more preferably at least 50 vol %.

With this configuration, a gas flow as developed by the exhalationbreath of a subject is delivered through the nasal airway of the subjectwhilst the oropharyngeal velum of the subject is closed, therebyproviding for the delivery of at least one therapeutic gas to the nasalairway and preventing inhalation of the at least one therapeutic gas.

FIG. 4 illustrates a delivery device in accordance with a fourthembodiment of the present invention.

The delivery device comprises a nosepiece 321 for fitting in one nostrilof a subject, in this embodiment to provide a fluid-tight sealtherewith, a mouthpiece 323 through which the subject exhales, and aflow channel 325 fluidly connecting the nosepiece 321 and the mouthpiece323.

The delivery device further comprises a gas generation unit 327 which isdisposed in the flow channel 325 and provides for the generation of anuptake enhancing gas, in this embodiment carbon dioxide, which isentrained by the gas flow, as developed by the exhalation breath, intothe nasal airway, and acts to enhance the uptake of an active substanceas delivered to the nasal airway, as will be described in more detailhereinbelow.

In this embodiment the gas generation unit 327 contains a powderedagent, here a mixture of a carbonate or bicarbonate salt, such as sodiumbicarbonate, and an acid, such as citric acid, which, when exposed tomoisture as contained in the exhaled breath, reacts to generate theuptake enhancing gas, here carbon dioxide. In addition to generating anuptake enhancing gas, the gas generation unit 327 has the particularbenefit of acting as a moisture trap, which reduces undesirablecondensation within the remainder of the delivery device. Suchcondensation is particularly problematic in the delivery of powderedsubstances.

In this embodiment the powdered agent is contained in an air permeablemember, typically a sachet, which can be replaced after one or more usesof the delivery device.

In this embodiment the gas generation unit 327 is disposed at anupstream end of the flow channel 325, such that substantially nocondensation of moisture from the exhalation breath occurs prior to theexhalation breath being exposed to the gas generation unit 327.

In one embodiment the gas generation unit 327 provides a gas flow whichhas a concentration of the uptake enhancing gas of at least 10 vol %,preferably at least 15 vol %, more preferably at least 20 vol %, stillmore preferably at least 30 vol %, yet more preferably at least 40 vol%, and yet still more preferably at least 50 vol %.

The delivery device further comprises a substance supply unit 329 forsupplying metered doses of an active substance for delivery to the nasalairway of the subject.

In one embodiment the substance supply unit 329 is configured to deliveran aerosol, either as a liquid or a powder aerosol, but in analternative embodiment could be configured to deliver a jet, that is, asa column of the substance, either as a liquid or powder jet.

In this embodiment the substance supply unit 329 comprises a dry powderdelivery unit which delivers metered doses of substance, as a drypowder, on actuation thereof. In one embodiment the substance supplyunit 329 could provide for delivery of substance from a container, suchas a capsule or blister.

In one alternative embodiment the substance supply unit 329 couldcomprise a mechanical delivery pump, in particular a liquid deliverypump or a powder delivery pump, which delivers metered doses ofsubstance, on actuation thereof.

In yet another alternative embodiment the substance supply unit 329could comprise an aerosol canister which delivers metered volumes of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In this embodiment the substance supply unit 329 is a multi-dose unitfor delivering a plurality of metered doses of the active substance. Inanother embodiment the substance supply unit 329 could be a single-doseunit for delivering a single metered dose of the active substance.

The substance supply unit 329 is pre-primeable, in this embodiment byloading a resilient element, and includes a breath-actuated releasemechanism which, when triggered, releases the resilient element andactuates the substance supply unit 329 to deliver a metered dose of theactive substance.

In this embodiment the trigger mechanism is configured to causeactuation of the substance supply unit 329 on generation of apredetermined flow rate through the flow channel 325.

In an alternative embodiment the trigger mechanism could be configuredto cause actuation of the substance supply unit 329 on generation of apredetermined pressure in the flow channel 325.

With this configuration, a gas flow as developed by the exhalationbreath of a subject is delivered through the nasal airway of the subjectwhilst the oropharyngeal velum of the subject is closed, with the velumbeing closed by the positive pressure as created in the oral cavity onexhalation, and a metered dose of an active substance is delivered intothe nasal airway on generation of a predetermined flow rate through thenasal airway, or in an alternative embodiment a predetermined pressurein the nasal airway. The gas flow as delivered through the nasal airwayincludes at least one uptake enhancing gas, in this carbon dioxide,which provides for enhanced uptake of the active substance, andinhalation of this gas is prevented by closure of the velum.

FIG. 5 illustrates a delivery device in accordance with a fifthembodiment of the present invention.

The delivery device comprises a nosepiece 421 for fitting in one nostrilof a subject, in this embodiment to provide a fluid-tight sealtherewith, a mouthpiece 423 through which the subject exhales, and aflow channel 425 fluidly connecting the nosepiece 421 and the mouthpiece423.

The delivery device further comprises a delivery unit 429 for deliveringmetered doses of an active substance and an uptake enhancing agent fordelivery to the nasal airway of the subject.

In this embodiment the uptake enhancing agent comprises a powderedsubstance, here a mixture of a carbonate or bicarbonate salt, such assodium bicarbonate, and an acid, such as citric acid, which, whenexposed to moisture at surfaces of the nasal mucosa, reacts to generatean uptake enhancing gas, here carbon dioxide, which provides forenhanced uptake of the active substance.

In one alternative embodiment the uptake enhancing agent could comprisean uptake enhancing gas, for example, carbon dioxide, which, whenexposed to the nasal mucosa, provides for enhanced uptake of the activesubstance.

In another alternative embodiment the uptake enhancing agent couldcomprise an uptake enhancing gas, for example, carbon dioxide, which isgenerated from a powdered substance, for example, a mixture of acarbonate or bicarbonate salt, such as sodium bicarbonate, and an acid,such as citric acid, which, when exposed to moisture in the exhaledbreath of the subject, reacts to generate the uptake enhancing gas,which provides for enhanced uptake of the active substance.

In this embodiment the delivery unit 429 is configured to deliver apowder aerosol, but in an alternative embodiment could be configured todeliver a powder jet, that is, as a powder column.

In this embodiment the substance supply unit 429 comprises a dry powderdelivery unit which delivers a metered dose of an active substance andan uptake enhancing agent on actuation thereof.

In this embodiment the active substance and the uptake enhancing agentare dry powders, and the uptake enhancing agent reacts with moisture onthe nasal mucosa to generate an uptake enhancing gas.

In the one alternative embodiment the active substance is a dry powderand the uptake enhancing agent is an accompanying gas.

In the other alternative embodiment the active substance is a dry powderand the uptake enhancing agent is a gas which is generated from thereaction of a powdered substance and moisture in the exhaled breath ofthe subject.

In this embodiment the substance supply unit 429 provides for deliveryof the active substance and the uptake enhancing agent, both as drypowders, from a container 431, such as a capsule or blister, where a gasflow as developed from the exhalation breath of the subject acts toentrain the powder from the container 431 following opening, typicallyrupturing, of the same.

In the one alternative embodiment the substance supply unit 429 providesfor delivery of the active substance, as a dry powder, and the uptakeenhancing agent, as a gas, from a container 431, such as a capsule orblister, where the uptake enhancing agent is a gas which is released onopening, typically rupturing, the container 431, and a gas flow asdeveloped from the exhalation breath of the subject acts to entrain thepowdered active substance from the container 431 following opening ofthe same.

In the other alternative embodiment the substance supply unit 429provides for delivery of the active substance, as a dry powder, and theuptake enhancing agent, as a gas, from a container 431, such as acapsule or blister, where the uptake enhancing gas is generated from apowdered substance contained within the container 431 on exposure tomoisture in the exhaled breath of the subject following opening,typically rupturing, of the container 431, and a gas flow as developedfrom the exhalation breath of the subject acts to entrain the activesubstance from the container 431 following opening of the same.

In the described embodiments the delivery unit 429 could be a multi-doseunit for delivering a plurality of metered doses of the active substanceand uptake enhancing agent, or a single-dose unit for delivering asingle metered dose of the active substance and uptake enhancing agent.

In the configuration of this embodiment, a gas flow as developed fromthe exhalation breath of a subject is delivered through the nasal airwayof the subject whilst the oropharyngeal velum of the subject is closed,with the velum being closed by the positive pressure as created in theoral cavity on exhalation, and a metered dose of an active substance andan uptake enhancing agent in combination is delivered into the nasalairway. In this embodiment the uptake enhancing agent reacts withmoisture on contact with surfaces in the nasal cavity such as togenerate an uptake enhancing gas thereat, here carbon dioxide, whichprovides for enhanced uptake of the active substance, and inhalation ofthis gas is prevented by closure of the velum.

In the configuration of the one alternative embodiment, a gas flow asdeveloped from the exhalation breath of a subject is delivered throughthe nasal airway of the subject whilst the oropharyngeal velum of thesubject is closed, with the velum being closed by the positive pressureas created in the oral cavity on exhalation, and a metered dose of anactive substance and an uptake enhancing agent, as a gas, is deliveredinto the nasal airway. In this embodiment the uptake enhancing gas, herecarbon dioxide, provides for enhanced uptake of the active substance,and inhalation of this gas is prevented by closure of the velum.

In the configuration of the other alternative embodiment, a gas flow asdeveloped from the exhalation breath of a subject is delivered throughthe nasal airway of the subject whilst the oropharyngeal velum of thesubject is closed, with the velum being closed by the positive pressureas created in the oral cavity on exhalation, and a metered dose of anactive substance and an uptake enhancing agent, as a gas, for example,carbon dioxide, is delivered into the nasal airway. In this embodimentthe uptake enhancing gas is generated by the reaction of a powderedsubstance, as contained within the container 431, with moisture from theexhalation breath of the subject, which provides for enhanced uptake ofthe active substance, and inhalation of this gas is prevented by closureof the velum.

FIG. 6 illustrates a delivery device in accordance with a sixthembodiment of the present invention.

The delivery device comprises a nosepiece 521 for fitting in one nostrilof a subject, in this embodiment to provide a fluid-tight sealtherewith, a mouthpiece 523 through which the subject exhales, and aflow channel 525 fluidly connecting the nosepiece 521 and the mouthpiece523.

The delivery device further comprises a gas supply unit 527 which isdisposed in the flow channel 525 such as to deliver at least onetherapeutic gas, in this embodiment carbon dioxide, to the gas flow asdeveloped by the exhalation breath at such a concentration as to providefor a therapeutic effect.

In one embodiment the gas supply unit 527 provides for a gas flow whichhas a concentration of therapeutic gas of at least 10 vol %, preferablyat least 15 vol %, more preferably at least 20 vol %, still morepreferably at least 30 vol %, yet more preferably at least 40 vol %, andyet still more preferably at least 50 vol %.

In this embodiment the gas supply unit 527 includes a gas supply 535 anda breath-actuated release mechanism 537 which, when triggered, actuatesthe gas supply 535 to supply a therapeutic gas to the gas flow asdeveloped through the flow channel 525. In one embodiment the gas supply535 comprises a pressurized container which is vented to the flowchannel 525 on triggering of the breath-actuated release mechanism 537.

In this embodiment the release mechanism 537 is configured to causeactuation of the gas supply unit 527 on generation of a predeterminedflow rate through the flow channel 525.

In an alternative embodiment the release mechanism 537 could beconfigured to cause actuation of the gas supply unit 527 on generationof a predetermined pressure in the flow channel 525.

With this configuration, a gas flow as developed by the exhalationbreath of a subject is delivered through the nasal airway of the subjectwhilst the oropharyngeal velum of the subject is closed, with the velumbeing closed by the positive pressure as created in the oral cavity onexhalation, and at least one therapeutic gas is delivered to the gasflow. The at least one therapeutic gas is thus entrained into the nasalairway and inhalation of the at least one therapeutic gas is preventedby closure of the velum.

FIG. 7 illustrates a delivery device in accordance with a seventhembodiment of the present invention.

The delivery device comprises a nosepiece 621 for fitting in one nostrilof a subject, in this embodiment to provide a fluid-tight sealtherewith, a mouthpiece 623 through which the subject exhales, and aflow channel 625 fluidly connecting the nosepiece 621 and the mouthpiece623.

The delivery device further comprises a gas supply unit 627 which isdisposed in the flow channel 625 such as to deliver at least one uptakeenhancing gas, in this embodiment carbon dioxide, to the gas flow asdeveloped by the exhalation breath of the subject at such aconcentration as to provide for enhanced uptake of an active substanceas delivered to the nasal airway, as will be described in more detailhereinbelow.

In one embodiment the gas supply unit 627 provides for a gas flow whichhas a concentration of an uptake enhancing gas of at least 10 vol %,preferably at least 15 vol %, more preferably at least 20 vol %, stillmore preferably at least 30 vol %, yet more preferably at least 40 vol%, and yet still more preferably at least 50 vol %.

In this embodiment the gas supply unit 627 includes a gas supply 635 anda breath-actuated release mechanism 637 which, when triggered, actuatesthe gas supply 635 to supply an uptake enhancing gas to the gas flow asdeveloped through the flow channel 625. In one embodiment the gas supply635 comprises a pressurized container which is vented to the flowchannel 625 on triggering of the breath-actuated release mechanism 637.

In this embodiment the release mechanism 637 is configured to causeactuation of the gas supply unit 627 on generation of a predeterminedflow rate through the flow channel 625.

In an alternative embodiment the release mechanism 637 could beconfigured to cause actuation of the gas supply unit 627 on generationof a predetermined pressure in the flow channel 625.

The delivery device further comprises a substance supply unit 639 forsupplying metered doses of an active substance for delivery to the nasalairway of the subject.

In one embodiment the substance supply unit 639 is configured to deliveran aerosol, either as a liquid or a powder aerosol, but in analternative embodiment could be configured to deliver a jet, that is, asa column of the substance, either as a liquid or powder jet.

In this embodiment the substance supply unit 639 comprises a dry powderdelivery unit which delivers metered doses of substance, as a drypowder, on actuation thereof. In one embodiment the substance supplyunit 639 could provide for delivery of substance from a container, suchas a capsule or blister.

In one alternative embodiment the substance supply unit 639 couldcomprise a mechanical delivery pump, in particular a liquid deliverypump or a powder delivery pump, which delivers metered doses ofsubstance, on actuation thereof.

In yet another alternative embodiment the substance supply unit 639could comprise an aerosol canister which delivers metered volumes of apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing substance, either as a suspension or solution.

In this embodiment the substance supply unit 639 is a multi-dose unitfor delivering a plurality of metered doses of the active substance. Inanother embodiment the substance supply unit 639 could be a single-doseunit for delivering a single metered dose of the active substance.

The substance supply unit 639 is pre-primeable, in this embodiment byloading a resilient element, and includes a breath-actuated releasemechanism which, when triggered, releases the resilient element andactuates the substance supply unit 639 to deliver a metered dose of theactive substance.

In this embodiment the trigger mechanism is configured to causeactuation of the substance supply unit 639 on generation of apredetermined flow rate through the flow channel 625.

In an alternative embodiment the trigger mechanism could be configuredto cause actuation of the substance supply unit 639 on generation of apredetermined pressure in the flow channel 625.

With this configuration, a gas flow as developed by the exhalationbreath of a subject is delivered through the nasal airway of the subjectwhilst the oropharyngeal velum of the subject is closed, with the velumbeing closed by the positive pressure as created in the oral cavity onexhalation, and, on generation of a predetermined flow rate through thenasal airway, or in an alternative embodiment a predetermined pressurein the nasal airway, at least one uptake enhancing gas is delivered tothe gas flow and a metered dose of an active substance is delivered intothe nasal airway. The at least one uptake enhancing gas, in thisembodiment carbon dioxide, provides for enhanced uptake of the activesubstance, and inhalation of this gas is prevented by closure of thevelum.

FIG. 8 illustrates a delivery device in accordance with an eighthembodiment of the present invention.

The delivery device comprises a nosepiece 721 for fitting in one nostrilof a subject, in this embodiment to provide a fluid-tight sealtherewith, and a mouthpiece 723 through which the subject exhales.

The delivery device further comprises a gas supply unit 727 which isfluidly connected to the nosepiece 721 such as to deliver at least onetherapeutic gas, in this embodiment carbon dioxide, to the nasal airwayat such a concentration as to provide for a therapeutic effect, as willbe described in more detail hereinbelow.

In one embodiment the gas supply unit 727 provides for a gas flow whichhas a concentration of a therapeutic gas of at least 10 vol %,preferably at least 15 vol %, more preferably at least 20 vol %, stillmore preferably at least 30 vol %, yet more preferably at least 40 vol%, and yet still more preferably at least 50 vol %.

In this embodiment the gas supply unit 727 includes a gas supply 735 anda release mechanism 737 which, when triggered, actuates the gas supply735 to deliver a therapeutic gas to the nosepiece 721 and into the nasalairway of the subject. In one embodiment the gas supply 735 comprises apressurized container which is vented to the nosepiece 721 on triggeringof the release mechanism 737.

The delivery device further comprises an exhalation sensor 741 which isfluidly connected to the mouthpiece 723 such as to detect exhalationthrough the mouthpiece 723 by the subject and operatively connected tothe release mechanism 737 of the gas supply unit 727, such as to providefor triggering of the gas supply unit 727 in response to exhalation bythe subject.

In this embodiment the exhalation sensor 741 is a flow sensor which isconfigured to cause actuation of the gas supply unit 727 on generationof a predetermined flow rate through the mouthpiece 723.

In an alternative embodiment the exhalation sensor 741 could be apressure sensor which is configured to cause actuation of the gas supplyunit 727 on generation of a predetermined pressure at the mouthpiece723.

With this configuration, a gas flow containing at least one therapeuticgas is delivered through the nasal airway of the subject in response toexhalation by the subject whilst the oropharyngeal velum of the subjectis closed, with the velum being closed by the positive pressure ascreated in the oral cavity on exhalation. In this way, at least onetherapeutic gas is delivered to the nasal airway, and inhalation of theat least one therapeutic gas is prevented by closure of the velum.

FIG. 9 illustrates a delivery device in accordance with a ninthembodiment of the present invention.

The delivery device comprises first and second nosepieces 821, 822 forfitting in the respective nostrils of a subject, in this embodiment toprovide a fluid-tight seal therewith, a mouthpiece 823 through which thesubject exhales, and a flow channel 825 which fluidly connects onenosepiece 821 and the mouthpiece 823.

The delivery device further comprises a scrubber 827 which is disposedin the flow channel 825 such as to remove one or more gases, in thisembodiment one or both of oxygen and nitrogen, from the exhaled air andprovide a gas flow which has an increased concentration of at least onegas, in this embodiment a concentration of carbon dioxide, which isincreased to a concentration which provides a therapeutic effect.

Alveolar air typically has a composition of N2—74.9 vol %, O2—13.6 vol %and CO2—5.3 vol %, which has a significantly increased concentration ofcarbon dioxide as compared to atmospheric air, which typically has thecomposition of N2—78.62 vol % O2—20.84 vol % and CO2—0.04 vol %. Throughuse of the scrubber 827 to remove nitrogen and oxygen from the exhaledair, the concentration of carbon dioxide in the delivered gas flow canbe increased significantly.

In one embodiment the scrubber 827 provides for a gas flow which has aconcentration of therapeutic gas of at least 10 vol %, preferably atleast 15 vol %, more preferably at least 20 vol %, still more preferablyat least 30 vol %, yet more preferably at least 40 vol %, and yet stillmore preferably at least 50 vol %.

In one embodiment the scrubber 827 could be configured to provide avisual indication, such as by way of changing colour, to indicate whenthe efficiency of the scrubber 827 has reduced below a predeterminedthreshold.

The delivery device further comprises a pressure regulator 845 which isfluidly connected to the other nosepiece 822 such as provide for apredetermined pressure regime in the nasal airway. In one embodimentproviding an increased pressure in the nasal airway acts to open ostiain the treatment of nasal conditions, such as sinus ostia in thetreatment of sinusitis.

In this embodiment the pressure regulator 845 comprises a progressiveflow resistor which provides a progressively increasing resistance tothe exhaled air from the exhalation breath of a subject. In oneembodiment the progressive flow resistor comprises an inflatable balloonwhich is manipulatable by the user to allow for control the pressurewithin the nasal cavity.

In another embodiment the pressure regulator 845 could be configured toprovide a predetermined flow resistance to the exhaled air flow.

In a further embodiment the pressure regulator 845 could be configuredto maintain a predetermined pressure regime in the nasal airway.

In one embodiment the pressure regulator 845 could be configured tomaintain a fixed pressure in the nasal airway, where as one of either ofa negative or positive pressure, in one embodiment through the use of anauxiliary pump.

In an alternative embodiment the pressure regulator 845 could beconfigured to generate an alternating pressure within the nasal airwayof a subject. By cycling the pressure within the nasal airway, improveddelivery of therapeutic gas to the paranasal sinuses, the tuba auditivaand the middle ears can be achieved.

In a further embodiment the delivery device could include a vibrationgenerator for generating vibrations in structures of the nasal airway ofthe subject, such as by the provision of sound waves of apredeterminable frequency, which act to improve communication throughthe ostia, in particular in ventilating the sinuses.

With this configuration, a gas flow as developed by the exhalationbreath of a subject is delivered through the nasal airway of the subjectwhilst the oropharyngeal velum of the subject is closed, therebyproviding for the delivery of at least one therapeutic gas to the nasalairway and preventing inhalation of the at least one therapeutic gas.

Finally, it will be understood that the present invention has beendescribed in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the invention asdefined by the appended claims.

For example, in one modification, the first to eighth embodiments couldbe modified in the manner of the ninth embodiment to include a second,outlet nosepiece and an associated pressure regulator.

Also, embodiments have been described specifically in relation to thegeneration of carbon dioxide as either a therapeutic or uptake enhancinggas. In other embodiments, which utilize nitric oxide as either thetherapeutic or uptake enhancing gas, the nitric oxide can be generatedfrom a mixture of sodium nitroprusside and an acid, such as citric acid,which, when exposed to moisture, as, for example, contained in theexhaled breath, reacts to generate the therapeutic gas. Also, in suchreactions, GRAS excipients can be utilized to control the rate of gasgeneration.

Further, in one alternative embodiment, in order to alter the relativeconcentrations of carbon dioxide, nitrogen and oxygen in the exhaledbreath of a subject, the exhaled breath could be passed through a liquidwhich is saturated with carbon dioxide, has substantially the samepartial pressure of oxygen as the exhaled breath and a reduced partialpressure or absence of nitrogen, which results in the carbon dioxideequilibrating into the gas phase, the nitrogen equilibrating into theliquid and the oxygen concentration remaining substantially unchanged.

1-8. (canceled)
 9. A method of delivering an uptake enhancing gas and asubstance to a nasal airway of a subject comprising: fitting a nosepieceinto one nostril of the subject; fitting a mouthpiece into a mouth ofthe subject, the mouthpiece fluidly connected to the nosepiece andconfigured to permit the subject to cause a flow of exhaled breaththrough the mouthpiece and through the nosepiece; causing the substanceto be delivered into the flow of exhaled breath; and causing the uptakeenhancing gas to be delivered into the flow of exhaled breath; whereinthe uptake enhancing gas is carbon dioxide.
 10. The method of claim 9,wherein the substance is delivered into the flow of exhaled breath froma container.
 11. The method of claim 10, wherein the container is acapsule.
 12. The method of claim 9, wherein the substance is a powder.13. The method of claim 9, wherein the substance is a liquid.
 14. Themethod of claim 9, wherein the substance is an aerosol.
 15. The methodof claim 9, further comprising causing a concentration of a gas withinthe flow of exhaled breath to be reduced.
 16. The method of claim 9,further comprising causing a concentration of a gas within the flow ofexhaled breath to be increased.
 17. The method of claim 9, furthercomprising causing an amount of a first gas to be added into the flow ofexhaled breath.
 18. The method of claim 17, wherein the first gas is agas that is not present in the flow of exhaled breath.
 19. A method ofdelivering an uptake enhancing gas and a substance to a nasal airway ofa subject comprising: fitting a nosepiece into one nostril of thesubject; fitting a mouthpiece into a mouth of the subject, themouthpiece fluidly connected to the nosepiece and configured to permitthe subject to cause a flow of exhaled breath through the mouthpiece andthrough the nosepiece; and causing the substance and the uptakeenhancing gas to be delivered into the flow of exhaled breath; whereinthe uptake enhancing gas is at least 10 vol. % of a combined flow of theflow of exhaled breath and the uptake enhancing gas.
 20. The method ofclaim 19, wherein the substance is delivered into the flow of exhaledbreath from a container.
 21. The method of claim 20, wherein thecontainer is a capsule.
 22. The method of claim 19, wherein thesubstance is a powder.
 23. The method of claim 19, wherein the substanceis a liquid.
 24. The method of claim 19, wherein the substance is anaerosol.
 25. The method of claim 19, wherein the uptake enhancing gas iscarbon dioxide.
 26. The method of claim 19, wherein the uptake enhancinggas is nitric oxide.
 27. The method of claim 19, wherein the uptakeenhancing gas is oxygen.
 28. The method of claim 19, wherein the uptakeenhancing gas is helium.
 29. The method of claim 19, further comprisingcausing a concentration of a gas within the flow of exhaled breath to bereduced.
 30. The method of claim 19, further comprising causing aconcentration of a gas within the flow of exhaled breath to beincreased.
 31. The method of claim 19, further comprising causing anamount of a first gas to be added into the flow of exhaled breath. 32.The method of claim 31, wherein the first gas is a gas that is notpresent in the flow of exhaled breath.